Affinage

HOXD13

Homeobox protein Hox-D13 · UniProt P35453

Length
343 aa
Mass
36.1 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HOXD13 is a homeodomain transcription factor that directly binds DNA at target gene promoters to control distal limb (autopod) patterning, chondrogenesis, and cell polarity (PMID:16314414, PMID:18407260). Through genome-wide and locus-specific binding it regulates a network of patterning and skeletal genes — activating EphA7/EPHA7 (PMID:12620993, PMID:16314414), Fhl1 (PMID:18758158), Hand2, Meis1/2, Bmp2/4 and other AP/PD axis loci (PMID:18407260), and the retinoic acid synthesis enzyme Raldh2 (PMID:19075394) — while repressing Gli3 (PMID:19925654) and, in cancer, SMAD1 (PMID:33521930). HOXD13 also drives the WNT/PCP pathway by inducing Wnt5a/5b to establish chondrocyte and perichondrial polarization in the growth plate (PMID:24161848). Its activity depends on a conserved homeodomain glutamine that dictates DNA-binding specificity: missense substitutions at this and other homeodomain residues abolish or re-target binding and transactivation, causing distinct syndactyly and brachydactyly phenotypes (I47L, Q317R/K, R306Q/G, T313R) (PMID:12620993, PMID:17236141, PMID:23995701, PMID:24789103, PMID:26581570). The recurrent disease allele is an exon-1 polyalanine tract expansion that causes synpolydactyly; expansion size correlates with phenotypic severity, and the mutant allele acts in a combined dominant-negative/gain-of-function manner — more severe than the null — by reducing retinoic acid synthesis and promoting ectopic interdigital chondrogenesis (PMID:8817328, PMID:9207113, PMID:9580668, PMID:19075394). Beyond development, HOXD13 binds replication origins, interacts with CDC6 to promote pre-replication complex assembly and accelerate DNA synthesis initiation, an activity blocked by geminin (PMID:19703996). The t(2;11) NUP98-HOXD13 fusion impairs hematopoietic differentiation and drives myelodysplastic syndrome and leukemia, in part by conferring Lmo2/Lyl1-dependent thymocyte self-renewal (PMID:10995009, PMID:15755899, PMID:30700838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1996 High

    Establishing that a discrete polyalanine tract expansion in HOXD13 causes synpolydactyly defined the gene's first human disease link and its two-exon homeodomain structure.

    Evidence Genomic sequencing and family segregation analysis across two SPD families with control chromosomes

    PMID:8817328

    Open questions at the time
    • Did not establish the molecular mechanism by which expansion perturbs protein function
    • No direct transcriptional readout
  2. 1997 High

    Correlating expansion size with phenotype severity argued the mutation is a specific gain of function rather than simple disruption.

    Evidence Molecular sizing of polyalanine expansions and genotype-phenotype correlation across 16 SPD families

    PMID:9207113

    Open questions at the time
    • Correlative, not mechanistic
    • Did not distinguish gain-of-function from dominant-negative at the protein level
  3. 1998 High

    Comparing the spdh expansion allele to a null allele in mouse showed the expanded protein is more deleterious than absence, defining a dominant-negative mechanism.

    Evidence Cloning of the spdh allele and phenotypic comparison of heterozygote/homozygote vs Hoxd13 null mice

    PMID:9580668

    Open questions at the time
    • Molecular target of the dominant-negative effect not identified
    • No biochemical demonstration of interference
  4. 2003 High

    An I47L homeodomain mutation that selectively loses binding at a subset of targets including EphA7 separated DNA-binding-dependent from interaction-dependent HOXD13 functions.

    Evidence In vitro DNA binding plus retroviral misexpression of WT, I47L, and DNA-binding-null IQN mutants in chick limbs

    PMID:12620993

    Open questions at the time
    • Identity of protein partners mediating DNA-binding-independent suppression unknown
    • Direct EphA7 promoter occupancy not yet shown
  5. 2005 High

    Direct in vivo binding and transactivation of the EphA7 promoter, lost in the I47L mutant, confirmed EphA7 as a bona fide HOXD13 target underlying its limb phenotype.

    Evidence ChIP in developing mouse limbs, EMSA, and luciferase transactivation assays

    PMID:16314414

    Open questions at the time
    • Cofactors at the EphA7 promoter not defined
    • Single target characterized
  6. 2000 Medium

    Discovery of the NUP98-HOXD13 fusion implicated HOXD13 homeodomain activity in leukemogenesis.

    Evidence 3'-RACE, RT-PCR and breakpoint mapping in a single AML patient

    PMID:10995009

    Open questions at the time
    • Single patient, no functional model
    • Causality not established at this stage
  7. 2005 High

    An NHD13 transgenic mouse demonstrated the fusion drives myelodysplastic syndrome with ineffective hematopoiesis and leukemic transformation, establishing causality.

    Evidence Transgenic mouse model with hematological/histological analysis and differentiation assays

    PMID:15755899

    Open questions at the time
    • Downstream effectors of differentiation block not identified here
    • Mechanism of apoptosis induction unresolved
  8. 2007 Medium

    Insertional mutagenesis defined collaborating loci (Meis1, Mn1, Gata2, Erg, Epor, miR29) that cooperate with NHD13 during transformation.

    Evidence Retroviral insertional mutagenesis screen with common insertion site mapping in NHD13 mice

    PMID:17545593

    Open questions at the time
    • Functional contribution of individual hits not validated
    • Single screen
  9. 2007 Medium

    A homeodomain Q317R mutation abolishing transactivation, and a polyalanine contraction allele, showed distinct HOXD13 lesions produce distinct digital phenotypes.

    Evidence Linkage, sequencing, luciferase transactivation assays and molecular modeling

    PMID:17236141

    Open questions at the time
    • No in vivo developmental model for these alleles
    • Single lab
  10. 2008 High

    Genome-wide ChIP-on-chip identified a broad HOXD13 target network controlling limb AP/PD and skeletal patterning, moving beyond single-gene models.

    Evidence ChIP-on-chip in developing mouse limbs with chick misexpression validation

    PMID:18407260

    Open questions at the time
    • Activation vs repression at individual loci not fully resolved
    • Cofactor requirements unknown
  11. 2008 Medium

    Direct regulation of Fhl1 added a muscle LIM protein to the HOXD13 target repertoire.

    Evidence EMSA, luciferase, and ChIP of endogenous Hoxd13-Fhl1 complex in rat limb

    PMID:18758158

    Open questions at the time
    • Phenotypic consequence of Fhl1 regulation not tested
    • Single target, single lab
  12. 2008 High

    A G220V mutation outside the homeodomain that impairs binding, stability and localization revealed a dominant loss-of-function/haploinsufficiency mechanism distinct from the polyalanine alleles.

    Evidence EMSA, transactivation, localization, protein stability and chick misexpression assays

    PMID:19060004

    Open questions at the time
    • Aggregation mechanism not detailed
    • Relationship to dominant-negative alleles not directly compared in vivo
  13. 2008 High

    Identifying Raldh2 as a direct target and rescuing synpolydactyly with retinoic acid pinned the polyalanine phenotype on reduced RA synthesis and ectopic interdigital chondrogenesis, demonstrating combined loss and gain of function.

    Evidence Mouse crossing, intrauterine RA rescue, primary chondrogenesis assays and direct target identification

    PMID:19075394

    Open questions at the time
    • Mechanism of the gain-of-function chondrogenic activity not fully molecularly defined
    • Sox6/Sox9 induction pathway not mapped
  14. 2009 High

    Demonstrating HOXD13 binds replication origins, interacts with CDC6, and accelerates DNA synthesis revealed a transcription-independent role in pre-replication complex assembly antagonized by geminin.

    Evidence ChIP at origins, co-IP of CDC6 and geminin, in vivo replication assay and BrdU/flow cytometry

    PMID:19703996

    Open questions at the time
    • Physiological context of origin licensing role unknown
    • Link to developmental function not established
  15. 2009 Medium

    Direct repression of Gli3 by HOXD13 connected the factor to hedgehog-pathway control during limb development.

    Evidence Luciferase, EMSA and ChIP in developing rat limb plus correlation in a clubfoot model

    PMID:19925654

    Open questions at the time
    • Repression mechanism (cofactors) unknown
    • Correlative model data
  16. 2009 Medium

    NHD13 was shown to block both B- and T-lymphoid differentiation with Hoxa cluster overexpression, broadening the fusion's impact across lineages.

    Evidence Flow cytometry, TCRb clonality RT-PCR and expression profiling in NHD13 mice

    PMID:19841179

    Open questions at the time
    • Causal driver among Hoxa genes not isolated
    • Single lab
  17. 2012 Medium

    A G11A allele that destabilizes both HOXD13 and GLI3R showed HOXD13 can influence patterning by modulating GLI3R stability.

    Evidence Novel mutation analysis, chick misexpression phenocopy, and in vitro GLI3R stability assays

    PMID:22373878

    Open questions at the time
    • Direct physical mechanism of GLI3R destabilization unknown
    • Single lab
  18. 2013 High

    Linking HOXD13 to Wnt5a/5b induction and PCP component localization defined a HOXD13→WNT5A→PCP axis controlling chondrocyte and perichondrial polarity.

    Evidence spdh/Wnt5a genetic comparison, in vitro Wnt5a/5b activation, PCP immunofluorescence and explant rescue

    PMID:24161848

    Open questions at the time
    • Direct vs indirect Wnt5a regulation not fully resolved
    • Mechanism of WNT/beta-catenin upregulation in perichondrium unclear
  19. 2013 High

    ChIP-seq of a Q317K mutant showed substitution of the conserved homeodomain glutamine re-targets HOXD13 toward a bicoid/PITX1 motif, demonstrating a neomorphic specificity switch distinct from milder Q317R loss-of-function.

    Evidence ChIP-seq in chicken mesenchymal stem cells with expression and in vivo overexpression validation

    PMID:23995701

    Open questions at the time
    • Functional consequences of redirected binding on limb morphology not fully mapped
    • Cofactor contribution to motif preference unknown
  20. 2014 Medium

    R306Q/R306G homeodomain mutations impairing transactivation defined the molecular basis of syndactyly type 1-c.

    Evidence Linkage, sequencing and luciferase transactivation assays

    PMID:24789103

    Open questions at the time
    • No in vivo model
    • Mechanism of partial vs complete loss not addressed
  21. 2015 Medium

    A homozygous T313R DNA-binding-null mutation, recessive in carriers, defined a complete loss-of-function allele causing severe brachydactyly with metacarpal-to-carpal transformation.

    Evidence Exome/Sanger sequencing with EMSA demonstrating loss of DNA binding

    PMID:26581570

    Open questions at the time
    • Single family/patient
    • No in vivo functional confirmation
  22. 2019 High

    Demonstrating NHD13 confers thymocyte self-renewal via an Lmo2/Lyl1 stem-cell programme, with Lyl1 required for AML transformation, identified the effectors of fusion-driven leukemic stemness.

    Evidence Serial transplantation, transcriptome analysis and Lyl1 knockout genetic cross

    PMID:30700838

    Open questions at the time
    • How NHD13 activates the Lmo2/Lyl1 programme mechanistically unresolved
    • Translation to human leukemia not established
  23. 2021 Medium

    Showing HOXD13 represses SMAD1 to block BMP4-induced EMT assigned it a metastasis-suppressor role in prostate cancer.

    Evidence Knockdown/knockout in prostate cancer cells, EMT assays and an in vivo bone metastasis model

    PMID:33521930

    Open questions at the time
    • Direct SMAD1 promoter occupancy not shown
    • Single lab
  24. 2022 High

    Identifying HOXD13 as a direct transcriptional antagonist of EWS::FLI1 in Ewing sarcoma extended its role to oncogenic transcriptional networks.

    Evidence CUT&RUN, RNA-seq, ChIP, CRISPRi, single-cell transcriptomics and migration assays

    PMID:35653119

    Open questions at the time
    • Therapeutic relevance not established
    • Mechanism of de-repression at shared sites not fully detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The protein partners and cofactors that mediate HOXD13's DNA-binding-independent functions, the molecular basis of its neomorphic and dominant-negative disease alleles, and the physiological role of its replication-licensing activity remain unresolved.
  • No structural model of HOXD13-cofactor complexes
  • Physiological context of origin-binding/CDC6 interaction unknown
  • Direct molecular mechanism of polyalanine gain-of-function not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-69306 DNA Replication 1
Partners
CDC6GMNNHOXA13NUP98

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 HOXD13 contains a 15-alanine polyalanine tract in exon 1; synpolydactyly (SPD) is caused by a 9-alanine duplication in this tract (expanding it to 24 alanines), confirmed in two unrelated SPD families and absent in 150 control chromosomes. The genomic structure of HOXD13 was established as two exons encoding a 335-amino-acid protein with a C-terminal homeodomain. Genomic sequencing, PCR-based mutation analysis, family segregation analysis Human molecular genetics High 8817328
1997 SPD phenotype severity (penetrance and expressivity in hands and feet) correlates significantly with the size of the polyalanine expansion in HOXD13 (7–14 extra residues tested), suggesting that expansion produces a specific gain of function in the mutant protein. Molecular sizing of polyalanine expansions across 16 SPD families; phenotype–genotype correlation analysis Proceedings of the National Academy of Sciences of the United States of America High 9207113
1998 A spontaneous mouse Hoxd13 mutation (spdh) carrying a 21-bp in-frame duplication expanding the polyalanine tract from 15 to 22 residues produces a phenotype more severe than null Hoxd13 mice, indicating the expanded polyalanine allele acts in a dominant-negative manner rather than as a simple loss-of-function. Molecular cloning of spdh allele, comparison of spdh heterozygote/homozygote phenotypes with Hoxd13 null mice Human molecular genetics High 9580668
2000 The t(2;11)(q31;p15) translocation generates NUP98-HOXD13 fusion transcripts encoding a protein with the FG-repeat region of NUP98 fused to the HOXD13 homeodomain; ectopic expression of the wild-type HOXD13 allele is also observed in the leukemia patient, implicating HOXD13 homeodomain activity in leukemogenesis. 3′-RACE, RT-PCR, chromosomal breakpoint mapping in an AML patient Leukemia Medium 10995009
2003 An I47L missense mutation in the HOXD13 homeodomain causes selective loss of DNA-binding at a subset of wild-type HOXD13 target sites (including the EphA7 locus) without dominant-negative or gain-of-function effects; retrovirus-mediated misexpression in chick limbs showed wild-type HOXD13 upregulates EphA7 in the autopod whereas HOXD13(I47L) cannot; both HOXD13(I47L) and a DNA-binding-null HOXD13(IQN) cause proximal limb shortening, suggesting functional suppression of anterior Hox genes does not require DNA binding and is mediated by protein–protein interactions. In vitro DNA-binding assays, retrovirus-mediated misexpression in developing chick limbs, in vivo comparison of wild-type, I47L, and IQN (DNA-binding null) mutant HOXD13 Development (Cambridge, England) High 12620993
2005 HOXD13 and HOXA13 directly bind multiple sites in the EphA7 promoter in vivo (confirmed by ChIP in developing mouse limbs and in vitro binding assays), and activate transcription from the EphA7 promoter; the HOXD13(I47L) brachydactyly mutation fails to bind the EphA7 promoter in vivo and fails to transactivate it. Promoter characterization, electrophoretic mobility shift assay (EMSA), ChIP in developing mouse limbs, luciferase transactivation assays, retrovirus-mediated misexpression in chick limbs The Journal of biological chemistry High 16314414
2005 NUP98-HOXD13 (NHD13) transgenic mice develop a uniformly fatal myelodysplastic syndrome (MDS) with peripheral cytopenias, bone marrow dysplasia, apoptosis, and transformation to acute leukemia; the NHD13 fusion gene inhibits megakaryocytic differentiation and increases bone marrow apoptosis, providing a mechanism for ineffective hematopoiesis. Transgenic mouse model, hematological and histological analysis, bone marrow differentiation assays Blood High 15755899
2007 A Q317R missense mutation in the HOXD13 homeodomain (substituting the highly conserved glutamine critical for DNA-binding specificity) abolishes HOXD13-mediated transactivation of the human EPHA7 promoter in luciferase assays, causing syndactyly type V. A 21-bp deletion causing polyalanine contraction of seven residues leads to a different digital anomaly (brachydactyly-syndactyly), not synpolydactyly. Linkage analysis, sequencing, luciferase transactivation assays, molecular modeling American journal of human genetics Medium 17236141
2007 Retroviral insertional mutagenesis in NUP98-HOXD13 transgenic mice identifies collaborating genes including Meis1, Mn1, Gata2, Erg, and Epor, as well as the miR29a/miR29b1 locus, which are upregulated during leukemic transformation from MDS, defining the genetic landscape of NHD13-mediated leukemogenesis. Retroviral insertional mutagenesis screen in NHD13 transgenic mice, common insertion site mapping, expression analysis Cancer research Medium 17545593
2008 HOXD13 directly regulates Fhl1 (skeletal muscle LIM protein 1) expression in developing rat embryo limbs: HOXD13 binds the Fhl1 promoter as shown by EMSA identifying a novel promoter element, luciferase transactivation assays, and ChIP of the endogenous Hoxd13–Fhl1 promoter complex from developing limbs. Immunofluorescence, luciferase assay, EMSA, chromatin immunoprecipitation (ChIP) in rat embryo limb tissue Cytogenetic and genome research Medium 18758158
2008 Hoxd13 binds in vivo in developing limbs to the loci of Hand2, Meis1, Meis2, Sfrp1, Barx1, Fbn1, Dach1, Bmp2, Bmp4, and Emx2 (identified by ChIP-on-chip with 248 gene loci total); Hoxd13 misexpression in chick limbs alters expression of the majority of these genes, establishing them as direct transcriptional targets involved in limb AP/PD axis and skeletal patterning. ChIP-on-chip genome-wide binding analysis in developing mouse limbs; retrovirus-mediated Hoxd13 misexpression in chick limbs with expression validation Developmental biology High 18407260
2008 A G220V missense mutation outside the HOXD13 homeodomain (in the N-terminal transcription-regulating domain) significantly impairs HOXD13 DNA binding and transcriptional activation/repression through HOXD13-responsive elements, reduces protein stability within cells, and causes partial cytosolic accumulation of subtle aggregates; in vivo chick limb misexpression confirms impaired capacity to perturb proximal limb skeletal development and activate the Hand2 target gene. This represents a dominant loss-of-function revealing HOXD13 haploinsufficiency. Luciferase transactivation assays, EMSA, immunofluorescence of protein localization, retrovirus-mediated misexpression in chick limbs, protein stability assays Human molecular genetics High 19060004
2008 Mutant Hoxd13 (Spdh allele, polyalanine expansion) causes polydactyly in synpolydactyly by inducing ectopic interdigital chondrogenesis both directly and indirectly via reduction of retinoic acid synthesis: Raldh2 (rate-limiting enzyme for RA synthesis in the limb) is identified as a direct Hoxd13 transcriptional target, RA levels are decreased in Spdh/Spdh limbs, intrauterine RA treatment restores pentadactyly, and mutant Hoxd13 promotes chondrogenesis associated with increased Sox6/Sox9 expression. Transgenic and crossing experiments demonstrate the Spdh allele combines loss and gain of function. Transgenic mouse crossing experiments, intrauterine RA rescue, primary cell chondrogenesis assays, gene expression analysis, identification of Raldh2 as direct Hoxd13 target The Journal of clinical investigation High 19075394
2009 HOXD13 binds all characterized human replication origins in vivo, interacts with the CDC6 DNA replication loading factor, promotes pre-replication complex (pre-RC) protein assembly at origins, stimulates DNA synthesis in an in vivo replication assay, and accelerates DNA synthesis initiation when overexpressed. Geminin interacts with HOXD13 and blocks HOXD13-mediated pre-RC assembly and DNA replication induction. ChIP at replication origins, co-immunoprecipitation (CDC6 interaction, geminin interaction), in vivo replication assay, BrdU incorporation/flow cytometry for DNA synthesis timing Molecular and cellular biology High 19703996
2009 NUP98-HOXD13 (NHD13) fusion gene expression impairs both B and T lymphoid differentiation: blocks pro-B to pre-B transition, causes a partial block at the DN2-to-DN3 thymocyte transition, and induces clonal expansion of thymocytes with incomplete TCRβ rearrangement (DJ but not VDJ). NHD13 thymi overexpress Hoxa cluster genes (Hoxa7, Hoxa9, Hoxa10). Flow cytometry of bone marrow and thymic compartments, degenerate RT-PCR for TCRβ rearrangement clonality, gene expression profiling in NHD13 transgenic mice Journal of immunology (Baltimore, Md. : 1950) Medium 19841179
2012 A novel G11A mutation in HOXD13 (outside the homeodomain and polyalanine tract) affects the intracellular half-life of the protein; misexpression of HOXD13(G11A) in chick limbs phenocopies human SPD; in vitro studies demonstrate this mutation has a destabilizing effect on GLI3R, revealing that HOXD13 can influence limb patterning by modulating GLI3R stability. Identification of novel mutation, retrovirus-mediated chick limb misexpression, in vitro GLI3R stability assays Human molecular genetics Medium 22373878
2013 HOXD13 regulates cell polarity in cartilage growth plate and perichondrium: spdh (Hoxd13 polyalanine expansion) metacarpal growth plates show defective chondrocyte polarization and failure of perichondrial cells to adopt flattened morphology. Wnt5a and Wnt5b are downregulated in spdh handplates; HOXD13 induces Wnt5a/5b expression in vitro; mislocalization of PCP components DVL2 and PRICKLE1 occurs in spdh metacarpals; WNT/β-CATENIN pathway is upregulated in the perichondral region. Non-cell autonomous rescue of cell polarity was achieved by providing HOXD13- or WNT5A-expressing cells to spdh limb explants. Mouse genetic analysis (spdh and Wnt5a knockout comparison), in vitro transactivation of Wnt5a/5b, immunofluorescence of PCP components, limb explant rescue experiments Developmental biology High 24161848
2013 Genome-wide ChIP-seq analysis of wild-type HOXD13 and a Q317K missense mutant in chicken mesenchymal stem cells reveals that the Q317K mutation shifts the genome-wide binding profile of HOXD13 toward a bicoid/PITX1 DNA-binding motif (due to substitution of the homeodomain glutamine conserved in most homeodomains). Gene expression analysis and in vivo overexpression studies confirm a partial conversion of HOXD13(Q317K) into a transcription factor with bicoid/PITX1 properties, which is not observed with the Q317R mutation associated with a milder phenotype. ChIP-seq in chicken mesenchymal stem cells, retroviral expression system, gene expression analysis, in vivo overexpression in chick Genome research High 23995701
2014 Mutations p.R306Q and p.R306G in the HOXD13 homeodomain cause syndactyly type 1-c; luciferase assays demonstrated that both mutations impair the transcriptional activation ability of HOXD13, establishing a link between homeodomain mutations and specific syndactyly subtype. Linkage analysis, sequencing, luciferase transactivation assays PloS one Medium 24789103
2015 A homozygous missense mutation c.938C>G (p.T313R) in the HOXD13 DNA-binding domain prevents HOXD13 binding to DNA in vitro as demonstrated by EMSA; heterozygous carriers are unaffected (non-penetrant), while the homozygous state causes severe brachydactyly with metacarpal-to-carpal transformation, consistent with complete loss of functional HOXD13 protein. Whole exome sequencing, Sanger sequencing for cosegregation, electrophoretic mobility shift assay (EMSA) for DNA binding American journal of medical genetics. Part A Medium 26581570
2019 NUP98-HOXD13 (NHD13) transgenic thymocytes exhibit self-renewal capacity (demonstrated by serial transplantation); NHD13-Tg thymocytes express a stem cell-like transcriptional programme including Lmo2 and its cofactor Lyl1; Lyl1 is essential for the stem cell-like gene expression programme and thymocyte self-renewal; loss of Lyl1 in NHD13-Tg mice accelerates T-ALL and eliminates AML transformation associated with loss of multipotent progenitors. Serial transplantation assays, transcriptome analysis, genetic cross of NHD13-Tg with Lyl1 knockout mice Leukemia High 30700838
2021 HOXD13 suppresses prostate cancer metastasis by inhibiting SMAD1 transcription, thereby preventing BMP4-induced epithelial-mesenchymal transition (EMT); HOXD13 depletion increases bone metastasis in a mouse metastatic model. HOXD13 knockdown/knockout in prostate cancer cells, in vitro EMT assays, in vivo bone metastasis mouse model, gene expression analysis of SMAD1 transcription International journal of cancer Medium 33521930
2007 The intergenic region between Evx2 and Hoxd13 functions as a boundary element that restricts enhancer association to the Hoxd13 promoter in a spatially and temporally differential manner during development of limbs, genital bud, and brain; the boundary comprises at least two functional units: a constitutive boundary element blocking transcriptional regulatory influences, and a regulatory element controlling the constitutive boundary in time and space. ES cell-based genetic deletion and replacement experiments dissecting the Evx2-Hoxd13 intergenic region PloS one Medium 17245451
2009 HOXD13 directly interacts with the Gli3 promoter in vivo in developing rat limb (confirmed by ChIP), and EMSA identifies a specific Hoxd13 binding site in the Gli3 promoter; low Hoxd13 expression correlates with increased Gli3 expression in an ICTEV (clubfoot) rat model, suggesting HOXD13 normally represses Gli3 transcription during limb development. Luciferase reporter assay, EMSA, ChIP from developing rat limb BMC musculoskeletal disorders Medium 19925654
2022 In Ewing sarcoma, EWS::FLI1 creates a de novo GGAA microsatellite enhancer in the HOXD locus driving HOXD13 expression; HOXD13 binds at established EWS::FLI1 binding sites and activates EWS::FLI1-repressed genes (mesenchymal/migratory programme), directly antagonizing EWS::FLI1 transcriptional repression and defining a mesenchymal transcriptional continuum in tumor cells. CUT&RUN, RNA-seq, ChIP for EWS::FLI1 binding sites, CRISPR interference, single-cell transcriptomics, migration assays, flow cytometry Clinical cancer research High 35653119

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Surfactant proteins SP-A and SP-D: structure, function and receptors. Molecular immunology 413 16213021
2004 Centrosome maturation and duplication in C. elegans require the coiled-coil protein SPD-2. Developmental cell 236 15068791
2005 NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood 198 15755899
1997 Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Proceedings of the National Academy of Sciences of the United States of America 171 9207113
2005 The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Molecular immunology 157 15589315
2005 SPD--a web-based secreted protein database. Nucleic acids research 154 15608170
2000 The spd-2 gene is required for polarization of the anteroposterior axis and formation of the sperm asters in the Caenorhabditis elegans zygote. Developmental biology 137 10885746
1996 Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families. Human molecular genetics 132 8817328
1998 Structure, biologic properties, and expression of surfactant protein D (SP-D). Biochimica et biophysica acta 122 9813367
2021 SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties. Frontiers in immunology 121 33542724
2021 Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases. Cancers 99 34204509
2007 Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome. American journal of human genetics 84 17236141
1998 A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly. Human molecular genetics 80 9580668
2012 Hoxd13 contribution to the evolution of vertebrate appendages. Developmental cell 65 23237954
2007 Retroviral insertional mutagenesis identifies genes that collaborate with NUP98-HOXD13 during leukemic transformation. Cancer research 61 17545593
2010 Role of surfactant protein A and D (SP-A and SP-D) in human antiviral host defense. Frontiers in bioscience (Scholar edition) 60 20036966
2013 Regulation of cell polarity in the cartilage growth plate and perichondrium of metacarpal elements by HOXD13 and WNT5A. Developmental biology 59 24161848
2005 Surfactant proteins SP-A and SP-D in human health and disease. Archivum immunologiae et therapiae experimentalis 59 16314824
2005 Blockade of B7-H1 with sPD-1 improves immunity against murine hepatocarcinoma. Anticancer research 58 16101143
2003 An I47L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function. Development (Cambridge, England) 55 12620993
2008 Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis. The Journal of clinical investigation 54 19075394
2005 Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs. The Journal of biological chemistry 52 16314414
2008 Hoxd13 binds in vivo and regulates the expression of genes acting in key pathways for early limb and skeletal patterning. Developmental biology 51 18407260
2016 Surfactant proteins, SP-A and SP-D, in respiratory fungal infections: their role in the inflammatory response. Respiratory research 49 27250970
2015 Role of soluble programmed death-1 (sPD-1) and sPD-ligand 1 in patients with cystic echinococcosis. Experimental and therapeutic medicine 48 26889250
2021 HOXD13 suppresses prostate cancer metastasis and BMP4-induced epithelial-mesenchymal transition by inhibiting SMAD1. International journal of cancer 45 33521930
2005 Hoxd13 expression in the developing limbs of the short-tailed fruit bat, Carollia perspicillata. Evolution & development 44 15733311
2001 Localization and functions of SP-A and SP-D at mucosal surfaces. Pediatric pathology & molecular medicine 44 11486736
2015 SPD-2/CEP192 and CDK Are Limiting for Microtubule-Organizing Center Function at the Centrosome. Current biology : CB 43 26119750
2001 Pneumocystis carinii pneumonia alters expression and distribution of lung collectins SP-A and SP-D. The Journal of laboratory and clinical medicine 42 11385364
2002 Serum SP-D is a marker of lung injury in rats. American journal of physiology. Lung cellular and molecular physiology 41 11880309
2020 Serum levels of soluble programmed death-1 (sPD-1) and soluble programmed death ligand 1(sPD-L1) in systemic lupus erythematosus: Association with activity and severity. Scandinavian journal of immunology 38 32243638
2019 Serum sPD-1 and sPD-L1 as Biomarkers for Evaluating the Efficacy of Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients. Clinical breast cancer 38 31176611
2016 Identification and characterization of suppressors of plant cell death (SPD) effectors from Magnaporthe oryzae. Molecular plant pathology 38 27301772
2013 Ligands and receptors of lung surfactant proteins SP-A and SP-D. Frontiers in bioscience (Landmark edition) 37 23747872
2012 Linking surfactant protein SP-D and IL-13: implications in asthma and allergy. Molecular immunology 35 23220073
2000 Heterogenous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation. Leukemia 35 10995009
2013 Chromosome movements promoted by the mitochondrial protein SPD-3 are required for homology search during Caenorhabditis elegans meiosis. PLoS genetics 34 23671424
2010 SP-D and regulation of the pulmonary innate immune system in allergic airway changes. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 20447075
2009 HOXD13 binds DNA replication origins to promote origin licensing and is inhibited by geminin. Molecular and cellular biology 34 19703996
2002 Lung surfactant protein D (SP-D) and the molecular diverted descendants: conglutinin, CL-43 and CL-46. Immunobiology 34 12396011
2024 SlWRKY81 regulates Spd synthesis and Na+/K+ homeostasis through interaction with SlJAZ1 mediated JA pathway to improve tomato saline-alkali resistance. The Plant journal : for cell and molecular biology 33 38468425
2017 sPD-L1 Expression is Associated with Immunosuppression and Infectious Complications in Patients with Acute Pancreatitis. Scandinavian journal of immunology 33 28513984
2021 Nanobubbles Containing sPD-1 and Ce6 Mediate Combination Immunotherapy and Suppress Hepatocellular Carcinoma in Mice. International journal of nanomedicine 31 34007176
2013 Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations. Genome research 29 23995701
2022 EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 28 35653119
2019 Soluble sPD-L1 and Serum Amyloid A1 as Potential Biomarkers for Lung Cancer. Journal of medical biochemistry 27 31156344
2014 Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families. PloS one 26 24789103
2008 A G220V substitution within the N-terminal transcription regulating domain of HOXD13 causes a variant synpolydactyly phenotype. Human molecular genetics 26 19060004
2021 HOXD13 promotes the malignant progression of colon cancer by upregulating PTPRN2. Cancer medicine 25 34272834
2014 The Caenorhabditis elegans pericentriolar material components SPD-2 and SPD-5 are monomeric in the cytoplasm before incorporation into the PCM matrix. Molecular biology of the cell 25 25103243
2011 A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance. Journal of human genetics 25 21814222
2021 Revisiting the Characteristics of Testicular Germ Cell Lines GC-1(spg) and GC-2(spd)ts. Molecular biotechnology 24 34125394
2018 Supramolecular Assembly of Human Pulmonary Surfactant Protein SP-D. Journal of molecular biology 24 29626540
2014 Joining the fingers: a HOXD13 Story. Developmental dynamics : an official publication of the American Association of Anatomists 24 24038517
2023 Enriched endogenous free Spd and Spm in alfalfa (Medicago sativa L.) under drought stress enhance drought tolerance by inhibiting H2O2 production to increase antioxidant enzyme activity. Journal of plant physiology 23 37988872
2012 Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model. Blood 22 22927245
2009 A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement. Journal of immunology (Baltimore, Md. : 1950) 22 19841179
2022 Upregulation of PD-1 Expression and High sPD-L1 Levels Associated with COVID-19 Severity. Journal of immunology research 21 35971391
2014 Surfactant protein SP-D modulates activity of immune cells: proteomic profiling of its interaction with eosinophilic cells. Expert review of proteomics 21 24697551
2010 Surfactant protein (SP)-A and SP-D as antimicrobial and immunotherapeutic agents. Recent patents on anti-infective drug discovery 21 20230362
2008 HOXD13 may play a role in idiopathic congenital clubfoot by regulating the expression of FHL1. Cytogenetic and genome research 21 18758158
2012 HOXA13 and HOXD13 expression during development of the syndactylous digits in the marsupial Macropus eugenii. BMC developmental biology 20 22235805
2002 Heterogeneous allele expression of pulmonary SP-D gene in rat large intestine and other tissues. Physiological genomics 20 12464693
2000 Generation of the NUP98-HOXD13 fusion transcript by a rare translocation, t(2;11)(q31;p15), in a case of infant leukaemia. British journal of haematology 20 10931000
2024 Adaptive tail-length evolution in deer mice is associated with differential Hoxd13 expression in early development. Nature ecology & evolution 19 38378804
2022 Centrosome maturation requires phosphorylation-mediated sequential domain interactions of SPD-5. Journal of cell science 19 35362532
2019 Soluble Ligand of the Immune Checkpoint Receptor (sPD-L1) in Blood Serum of Patients with Renal Cell Carcinoma. Bulletin of experimental biology and medicine 19 30627905
2007 Evx2-Hoxd13 intergenic region restricts enhancer association to Hoxd13 promoter. PloS one 19 17245451
2007 Association of hypospadias with hypoplastic synpolydactyly and role of HOXD13 gene mutations. Urology 18 17656229
2022 SP-D and CC-16 Pneumoproteins' Kinetics and Their Predictive Role During SARS-CoV-2 Infection. Frontiers in medicine 17 35211479
2007 Synpolydactyly and HOXD13 polyalanine repeat: addition of 2 alanine residues is without clinical consequences. BMC medical genetics 17 18072967
2017 Expression of ODC1, SPD, SPM and AZIN1 in the hypothalamus, ovary and uterus during rat estrous cycle. General and comparative endocrinology 16 28315656
2015 Decidual expression and localization of human surfactant protein SP-A and SP-D, and complement protein C1q. Molecular immunology 16 25829244
2015 A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation. American journal of medical genetics. Part A 16 26581570
2020 GALNT10 promotes the proliferation and metastatic ability of gastric cancer and reduces 5-fluorouracil sensitivity by activating HOXD13. European review for medical and pharmacological sciences 15 33275228
2010 Identification of genes downstream of the Shh signalling in the developing chick wing and syn-expressed with Hoxd13 using microarray and 3D computational analysis. Mechanisms of development 15 20708683
2021 Soluble programmed cell death protein 1 (sPD-1) and the soluble programmed cell death ligands 1 and 2 (sPD-L1 and sPD-L2) in lymphoid malignancies. European journal of haematology 14 33721375
2010 Polyalanine repeat expansion mutation of the HOXD13 gene in a Chinese family with unusual clinical manifestations of synpolydactyly. European journal of medical genetics 14 20974300
2020 FaPAO5 regulates Spm/Spd levels as a signaling during strawberry fruit ripening. Plant direct 13 32355906
2020 TLR2/6 signaling promotes the expansion of premalignant hematopoietic stem and progenitor cells in the NUP98-HOXD13 mouse model of MDS. Experimental hematology 13 32652111
2020 A novel miR-7156-3p-HOXD13 axis modulates glioma progression by regulating tumor cell stemness. International journal of biological sciences 13 33162825
2019 Quantification of surfactant protein D (SPD) in human serum by liquid chromatography-mass spectrometry (LC-MS). Talanta 13 31171213
2012 An N-terminal G11A mutation in HOXD13 causes synpolydactyly and interferes with Gli3R function during limb pre-patterning. Human molecular genetics 13 22373878
2012 A novel non-synonymous mutation in the homeodomain of HOXD13 causes synpolydactyly in a Chinese family. Clinica chimica acta; international journal of clinical chemistry 13 22374128
2020 SPD_1495 Contributes to Capsular Polysaccharide Synthesis and Virulence in Streptococcus pneumoniae. mSystems 12 32098834
2020 Functional characterization of the different oligomeric forms of human surfactant protein SP-D. Biochimica et biophysica acta. Proteins and proteomics 12 32325256
2019 The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1. Leukemia 12 30700838
2017 Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing. Molecular medicine reports 12 28498426
2015 Expression of surfactant proteins SP-A and SP-D in murine decidua and immunomodulatory effects on decidual macrophages. Immunobiology 12 26421960
2012 SP-A and SP-D in host defense against fungal infections and allergies. Frontiers in bioscience (Elite edition) 12 22201901
2022 The correlation of serum sPD-1 and sPD-L1 levels with clinical, pathological characteristics and lymph node metastasis in nonsmall cell lung cancer patients. Turkish journal of medical sciences 11 36326416
2021 Mutant Idh2 Cooperates with a NUP98-HOXD13 Fusion to Induce Early Immature Thymocyte Precursor ALL. Cancer research 11 34321240
2021 Association of PD-L1 gene polymorphisms and circulating sPD-L1 levels with HBV infection susceptibility and related liver disease progression. Gene 11 34478821
2015 sec-Butylpropylacetamide (SPD) has antimigraine properties. Cephalalgia : an international journal of headache 11 26568161
2007 Mouse embryonic stem cells that express a NUP98-HOXD13 fusion protein are impaired in their ability to differentiate and can be complemented by BCR-ABL. Leukemia 11 17377591
2025 Serum KL-6 and SP-D: Markers of Lung Function in Autoimmune-Related Interstitial Lung Diseases. International journal of molecular sciences 10 39940859
2023 Sex-dependent PD-L1/sPD-L1 trafficking in human endothelial cells in response to inflammatory cytokines and VEGF. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 10 37068331
2009 The expression of Gli3, regulated by HOXD13, may play a role in idiopathic congenital talipes equinovarus. BMC musculoskeletal disorders 10 19925654
2007 Novel mutations of the HOXD13 gene in hand and foot malformations. International surgery 10 18399101

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